Styrenic compounds, methods of making the same, and uses thereof in the preparation of medicaments for the treatment of drug addiction and alleviation of withdrawal symptoms

Abstract

Styrene compounds, methods for preparing the same, and uses thereof in the preparation of medicaments for treating drug addiction and alleviating withdrawal symptoms. Disclosed are styrene compounds having the structure of Formula III: or stereoisomers, deuterated compounds, or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 are each independently selected from hydrogen, hydroxyl, alkoxy, or phosphate; L is selected from carbonyl or methylene; X is selected from O; R 4 is selected from hydrogen, C1-C 10 linear or branched alkyl, C3-C 10 cycloalkyl, aralkyl, hydroxyalkyl, or carbonylalkyl. The styrene compounds of the present invention not only intervene in METH-induced reward behavior, but also improve negative emotional behaviors such as depression and anxiety commonly seen during withdrawal, and have a dual value of significantly alleviating both addiction symptom formation and withdrawal symptoms. Disclosed are uses of the styrene compounds or stereoisomers, deuterated compounds, or pharmaceutically acceptable salts thereof in the preparation of medicaments for preventing and / or treating methamphetamine addiction and alleviating depression and anxiety-like behaviors caused by methamphetamine withdrawal.

Description

Technical Field

[0001] This invention relates to styrene compounds, their preparation methods, and their use in the preparation of drugs for treating drug addiction and relieving withdrawal symptoms. Background Technology

[0002] Methamphetamine (METH) is a potent central nervous system stimulant. Long-term abuse can lead to severe addictive behaviors, characterized by intense cravings, enhanced drug-seeking behavior, and an extremely high relapse rate after withdrawal. During withdrawal, METH users often experience significant negative emotions such as anxiety, depression, and irritability. Currently, there is a severe lack of medications for treating METH addiction that can effectively alleviate these negative emotions.

[0003] In addictive behavior research, Conditioned Place Preference (CPP) is an important experimental model for assessing drug-induced reward memory. METH can significantly induce CPP behavior in animals, reflecting its strong reward effect. However, during the withdrawal phase, METH users often experience significant negative emotions such as anxiety, depression, and irritability, which severely interfere with the withdrawal process and are important factors inducing relapse. These withdrawal-related mental symptoms not only increase the psychological burden on users but also deepen their dependence on the drug, forming a vicious cycle of addiction-withdrawal-relapse. Therefore, reducing addiction and dependence is crucial for improving negative emotions such as anxiety and depression, and for achieving successful METH withdrawal. Currently, there are no truly effective drugs for treatment in clinical practice.

[0004] Currently, there is a lack of medications specifically for METH addiction, and even more so, a lack of effective and reliable treatments that simultaneously address both the formation of METH addiction and the related symptoms of mental and behavioral disorders during withdrawal. Traditional antidepressants or anti-anxiety medications, such as selective serotonin reuptake inhibitors (SSRIs), while providing some relief of mood symptoms, have slow onset of action, limited efficacy, and various adverse reactions. This leads to poor patient compliance, short treatment duration, and difficulty in achieving satisfactory therapeutic results. There is an urgent need to develop novel compounds that can improve both addictive symptoms and negative emotions such as anxiety / depression, while also possessing high safety and few side effects, to eliminate METH addiction and alleviate negative emotions such as anxiety / depression, thereby achieving successful METH withdrawal. Summary of the Invention

[0005] Preliminary research by the inventors revealed that 4-hydroxy-3,5-dimethoxycinnamic acid (sinapic acid), a phenolic acid compound derived from natural plants, has a certain alleviating effect on methamphetamine addiction. However, the efficacy was insufficient and not significant, and it was unknown whether it could improve the depressive / anxiety-like behaviors caused by methamphetamine withdrawal. Therefore, the inventors designed and synthesized a series of styrene compounds, including methyl sinapicate phosphate, propyl sinapicate phosphate, and glyceryl sinapicate, and systematically optimized their efficacy and metabolic stability, exhibiting good neuropharmacological properties. Among them, compound I-15 is a representative compound, showing good efficacy against methamphetamine addiction and withdrawal-induced depressive / anxiety-like behavioral abnormalities.

[0006] The technical solution of the present invention is as follows:

[0007] Styrene compounds or their stereoisomers, deuterated derivatives, and pharmaceutically acceptable salts with structures as shown in Formula III:

[0008]

[0009] III;

[0010] Among them, R 1 R 2 R 3 Each group is independently selected from hydrogen, hydroxyl, alkoxy, or phosphate ester groups; L is selected from carbonyl ( ) or methylene (CH2); X is selected from O; R 4 Selected from hydrogen, C1 to C 10 Straight-chain or branched alkyl groups, C3-C 10 Cycloalkyl, aromatic alkyl, hydroxyalkyl, or carbonylalkyl;

[0011] But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-pentyl ( ), cyclohexyl, phenyl, benzyl, , 1,2-Propanediol ( ), ;R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

[0012] Preferred, R 1 Selected from C1 to C4 alkoxy groups;

[0013] R 2 Selected from hydroxyl, dihydroxyphosphoryloxy ( ),Mode The dialkoxyphosphoryloxy group shown; R 5 Selected from C1-C4 alkyl, benzyl, R 6 Selected from hydrogen, C1-C4 alkyl, and benzyl;

[0014] R 3 Selected from C1 to C4 alkoxy groups;

[0015] L is selected from carbonyl or methylene;

[0016] X is selected from O;

[0017] R 4 Selected from hydrogen, C1-C6 straight-chain or branched alkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C6-C 10 Arylalkyl;

[0018] But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-pentyl ( ), cyclohexyl, phenyl, benzyl, phenethyl ( ), phenylpropyl ( ), 1,2-propanediol, ;R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

[0019] Further preferred, R 1 Selected from methoxy groups;

[0020] R 2 Selected from hydroxyl, dihydroxyphosphoryloxy ( ),Mode The dialkoxyphosphoryloxy group shown; R 5 Selected from C1-C4 alkyl, benzyl, R 6 Selected from hydrogen, C1-C4 alkyl, and benzyl;

[0021] R 3 Selected from methoxy groups;

[0022] L is selected from carbonyl or methylene;

[0023] X is selected from O;

[0024] R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, 3-hydroxypropyl ( ), phenethyl, phenylpropyl, 3,5-di-tert-butyl-4-hydroxybenzoyl ( );

[0025] But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, phenethyl, phenylpropyl; R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

[0026] Further optimized, R 1 Selected from methoxy groups;

[0027] R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, R 6 Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, and benzyl;

[0028] R 3 Selected from methoxy groups;

[0029] L is selected from carbonyl group;

[0030] X is selected from O;

[0031] R 4 Selected from methyl, ethyl, n-propyl, isopropyl, cyclobutyl, 3-hydroxypropyl, phenethyl, and phenylpropyl;

[0032] R 1 Selected from methoxy groups;

[0033] R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, R 6 Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, and benzyl;

[0034] R 3 Selected from methoxy groups;

[0035] L is selected from methylene;

[0036] X is selected from O;

[0037] R 4 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclobutyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, acetyl, 3,5-di-tert-butyl-4-hydroxybenzoyl, dimethyl malate, morpholinyl, thiomorpholinyl. ;

[0038] But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from methyl, ethyl, n-propyl, isopropyl; R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

[0039] As one of the technical solutions of the present invention, when L in a styrene compound with a structure as shown in Formula III is selected from a carbonyl group, the styrene compound with a structure as shown in Formula I, or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0040] ;

[0041] Among them, R 1 R 2 R 3 R 4 X is as described above.

[0042] As one of the technical solutions of the present invention, when L of a styrene compound with a structure as shown in Formula III is selected from methylene, a styrene compound with a structure as shown in Formula II or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0043] ;

[0044] Among them, R 1 R 2 R 3 R 4 As mentioned above.

[0045] C1 to C4 alkyl groups can be specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0046] C3 to C6 cycloalkyl groups can be specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] C1 to C4 alkoxy groups can be specifically selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

[0048] Specifically, you can choose from... , , , , , .

[0049] Preferred options include styrene compounds or their stereoisomers, or pharmaceutically acceptable salts, with the following structures:

[0050] I-02, I-15, I-18, I-21, I-22, I-23,

[0051] I-24, I-25, I-26,

[0052] I-27, I-28, I-29,

[0053] I-30, I-31, II-03,

[0054] II-04, II-05.

[0055] As a preferred embodiment of the present invention, styrene compounds or their stereoisomers, or pharmaceutically acceptable salts, with the following structures are used:

[0056] .

[0057] Another object of the present invention is to provide a method for preparing the styrene compounds described above, according to L, R 2 ,R 4 The differences include:

[0058] When L is selected from carbonyl, R 2 Selected from hydroxyl, R 1 R 3When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows:

[0059] ;

[0060] Among them, R 4 As mentioned above;

[0061] Including: 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in Formula IIIa.

[0062] The R mentioned 4 Excess OH, generally, 4-hydroxy-3,5-dimethoxycinnamic acid with R 4 The molar ratio of OH is 1:1.2 to 1:4.

[0063] The reaction solvent is tetrahydrofuran or dichloromethane; the esterification reaction temperature is the reflux temperature corresponding to the reaction system.

[0064] The esterification reaction can be carried out using concentrated sulfuric acid as a catalyst; the concentrated sulfuric acid, calculated as H2SO4, has a molar ratio of 0.98:1 to 1:1 with 4-hydroxy-3,5-dimethoxycinnamic acid; the esterification reaction can also be carried out using DMAP as a catalyst in the presence of EDC·HCl, with a molar ratio of DMAP to 4-hydroxy-3,5-dimethoxycinnamic acid of 0.1:2 to 0.2:2; when EDC·HCl is present, the molar ratio of EDC·HCl to 4-hydroxy-3,5-dimethoxycinnamic acid is 1.1:1.

[0065] When L is selected from carbonyl, R 2 Selected from formula The dialkoxyphosphoryloxy group shown, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows:

[0066] ;

[0067] Among them, R 2 R 4 R 5 R 6 As mentioned above;

[0068] include:

[0069] Step (1), 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIa;

[0070] Step (2): Using carbon tetrachloride as the reaction solvent, in the presence of triethylamine, a styrene compound with the structure shown in formula IIIa reacts with... The dialkyl phosphite shown undergoes a phosphorylation reaction to generate a styrene-like compound with the structure shown in Formula IIIb.

[0071] In step (2), the molar ratio of the styrene compound with structure as shown in formula IIIa to triethylamine is 1:1.2 to 1:1.4. The molar ratio of the dialkyl phosphite shown is 1:1.3 to 1:2; the phosphorylation reaction is carried out at 0°C for 1 hour, then transferred to room temperature (25±5°C) for further reaction.

[0072] When L is selected from carbonyl, R 2 Selected from dihydroxyphosphoryloxy, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows:

[0073] ;

[0074] Among them, R 4 As mentioned above;

[0075] include:

[0076] Step (1), 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIa;

[0077] Step (2): Using dichloromethane as the reaction solvent, in the presence of triethylamine, a styrene compound with the structure shown in Formula IIIa reacts with phosphorus oxychloride to generate a styrene compound with the structure shown in Formula IIIc.

[0078] When L is selected from methylene, R 2 Selected from formula The dialkoxyphosphoryloxy group shown, R 1 R 3 Each is independently selected from methoxy groups, and X is selected from O and R. 4 When hydrogen is selected, the synthetic route is as follows:

[0079] ;

[0080] Among them, R 5 R 6 As mentioned above;

[0081] include:

[0082] Step (1), Reduction reaction: using diisobutylaluminum hydride as a reducing agent and toluene as a reaction solvent, ethyl 3,5-dimethoxy-4-hydroxycinnamate (compound 4) undergoes a reduction reaction to generate compound 5; wherein, the ratio of compound 4 to diisobutylaluminum hydride is 1:3 mmol / mL, and the temperature of the reduction reaction is 0℃;

[0083] Step (2), Phosphorylation reaction: Using carbon tetrachloride as the reaction solvent, in the presence of triethylamine, compound 5 reacts with... The dialkyl phosphite shown undergoes a phosphorylation reaction to generate a styrene-like compound with the structure shown in Formula IIId; wherein, the molar ratio of compound 5 to triethylamine is 1:1.2 to 1:1.4, and compound 5 is reacted with... The molar ratio of dialkyl phosphite shown is 1:1.3 to 1:2; the phosphorylation reaction is carried out at 0℃ for 1 hour, then transferred to room temperature (25±5℃) for further reaction.

[0084] When L is selected from methylene, R 2 Selected from hydrogen, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows:

[0085] ;

[0086] R 4 As mentioned above;

[0087] include:

[0088] Step (1), Reduction reaction: Using diisobutylaluminum hydride as a reducing agent and toluene as a reaction solvent, ethyl 3,5-dimethoxy-4-hydroxycinnamate (compound 4) undergoes a reduction reaction to generate compound 5;

[0089] Step (2), esterification reaction: using dichloromethane as the reaction solvent and DMAP as the catalyst, in the presence of DCC, compound 5 reacts with R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIe;

[0090] The molar ratio of DMAP to 4-hydroxy-3,5-dimethoxycinnamic acid is 0.1:2 to 0.2:2; when DCC is present, the molar ratio of DCC to 4-hydroxy-3,5-dimethoxycinnamic acid is 1.2:1.

[0091] In the METH-induced CPP model, the styrene compounds described in this invention significantly reduced the METH-induced CPP score, suggesting that they can effectively inhibit the formation of METH reward memory and exert an anti-addiction effect. Of particular note is that, even with a significantly reduced dosage, the injectable administration method still demonstrated good efficacy, proving the potential of the styrene compounds in alleviating methamphetamine addiction.

[0092] Meanwhile, in the METH withdrawal model, the styrene compounds also demonstrated good effects in improving depression- or anxiety-related behaviors. Experimental results showed that styrene compounds significantly reduced immobility time in mice during the forced swimming test (FST) and tail suspension test (TST), suggesting their role in alleviating depression / anxiety-like behaviors. In the open field test (OFT) and elevated cross maze test (EPM), increased activity time in the central area and open arms indicated good anti-anxiety potential. Of particular note is that, even with significantly reduced dosages, styrene compounds still exhibited good efficacy when administered by injection, demonstrating their potential application in alleviating methamphetamine-induced depression / anxiety-like behaviors.

[0093] This indicates that the styrene compounds of the present invention, administered by gavage at higher doses or by injection at lower doses, can not only intervene in METH-induced reward behavior, but also improve negative emotional behaviors such as depression / anxiety that are common during withdrawal, thus having the dual value of significantly alleviating addiction symptoms and withdrawal symptoms.

[0094] Another object of the present invention is to provide the use of the aforementioned styrene compounds or their stereoisomers, deuterated compounds, or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of methamphetamine addiction and for the relief of depression and anxiety-like behaviors following methamphetamine withdrawal.

[0095] Another object of the present invention is to provide a pharmaceutical composition comprising, as a main active ingredient, the aforementioned styrene compound or its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, and formulated into a pharmaceutically acceptable preparation with pharmaceutically acceptable excipients.

[0096] The preparations are tablets, capsules, granules, solutions, suspensions, or injections.

[0097] Another object of the present invention is the use of styrene compounds or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts with the structure shown in Formula III in the preparation of medicaments for the prevention and / or treatment of methamphetamine addiction and for the relief of depressive and anxiety-like behaviors following methamphetamine withdrawal.

[0098] ;

[0099] Among them, R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from isopropyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, dimethyl malate ( ); R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L from carbonyl, X from NH, R 4 The derivative is selected from hydrogen, ethyl, n-propyl, cyclopropyl, phenyl, phenethyl, or X is selected from N, and X is related to R. 4 Cyclic formation to form morpholino or thiomorpholino; R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L from methylene, X from carbonyl, R 4 Selected from hydrogen; R 1 Selected from methoxy, R 2 Selected from acetoxy ( ), R 3 Selected from methoxy, L from methylene, X from carbonyl, R 4 Selected from acetyl groups.

[0100] Another object of the present invention is the use of styrene compounds or their stereoisomers, deuterated compounds, or pharmaceutically acceptable salts with the structure shown below in the preparation of medicaments for the prevention and / or treatment of methamphetamine addiction and for the relief of depressive and anxiety-like behaviors following methamphetamine withdrawal.

[0101] I-01, I-03 I-04,

[0102] I-05, I-06, I-07,

[0103] I-08, I-09, I-10, I-11, I-12, I-13,

[0104] I-14, I-16, I-17,

[0105] I-19, I-20, II-01,

[0106] II-02.

[0107] Another object of the present invention is the use of styrene compounds or their stereoisomers, deuterated compounds, or pharmaceutically acceptable salts with the structure shown below in the preparation of medicaments for the prevention and / or treatment of methamphetamine addiction and for the relief of depressive and anxiety-like behaviors following methamphetamine withdrawal.

[0108] .

[0109] The dosage form of the drug is tablets, capsules, granules, solutions, suspensions, or injections. Attached Figure Description

[0110] Figure 1 The pharmacodynamic effects of compounds I-3, I-08, I-15, I-17, and I-23 on methamphetamine-induced conditional position preference were investigated. The Students' T-test was used for group analysis. *: p < 0.05; **: p < 0.01; ns: p > 0.05, indicating no statistically significant difference.

[0111] Figure 2 The pharmacodynamic effects of compounds I-09, II-02, and I-26 on methamphetamine-induced conditional position preference were determined. The Students' T-test was used for group analysis; *: p < 0.05; ns: p > 0.05, indicating no statistically significant difference.

[0112] Figure 3 The efficacy of compounds I-3, I-08, I-15, I-17, and I-23 in inducing depressive-like behaviors during methamphetamine withdrawal was evaluated. A: time to immobility during forced swimming; B: time to immobility during tail suspension. The independent students' t-test was used for analysis. *: p < 0.05; **: p < 0.01; ns: p > 0.05, indicating no statistically significant difference.

[0113] Figure 4 The efficacy of compounds I-09, II-02, and I-26 in inducing depressive-like behaviors during methamphetamine withdrawal.

[0114] Figure 5 The efficacy of compounds I-09, II-02, I-15, and I-26 in inducing anxiety-like behaviors during methamphetamine withdrawal.

[0115] Figure 6The effects of dosage and administration method of compound I-15 on the positional preference of methamphetamine induction conditions were investigated. The Students' T-test was used for group analysis. *: p<0.05; **: p<0.01; ns: p>0.05, and the differences were not statistically significant.

[0116] Figure 7 The efficacy of compound I-15 in inducing depressive-like behavior during methamphetamine withdrawal was evaluated by dosage and administration method. A: time to immobility during forced swimming; B: time to immobility during tail suspension; LA: 4-hydroxy-3,5-dimethoxycinnamic acid; FLX: fluoxetine. The independent students' t-test was used for analysis. *: p<0.05; **: p<0.01; ns: p>0.05, indicating no statistically significant difference.

[0117] Figure 8 The efficacy of compound I-15 in treating methamphetamine withdrawal-induced anxiety-like behavior was evaluated by dosage and administration method. A: central dwell time in the open field test; B: total distance traveled in the open field test; C: open arm dwell time in the elevated cross maze; D: total distance traveled in the elevated cross maze; LA: 4-hydroxy-3,5-dimethoxycinnamic acid; FLX: fluoxetine. The independent students' t-test was used for analysis. *: p < 0.05; **: p < 0.01; ns: p > 0.05, indicating no statistically significant difference. Detailed Implementation

[0118] The technical solution of the present invention will be further described below with reference to the embodiments. The embodiments can enable those skilled in the art to have a more comprehensive understanding of the present invention, but do not limit the present invention to the scope of the embodiments.

[0119] Example 1

[0120] Preparation of compound I-01

[0121]

[0122] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2-pentanol (432 mg, 6 mmol) and sulfuric acid (98%, 196 mg, 1.96 mmol) were added dropwise. The mixture was heated to reflux at 66 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to obtain 541 mg of compound I-01 (white solid, yield 91.9%). 1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J = 15.9 Hz, 1H), 6.79 (s,2H), 6.31 (d, J = 15.9 Hz, 1H), 5.79 (s, 1H), 5.07 (dq, J = 12.1, 6.3 Hz,1H), 3.94 (s, 6H), 1.75-1.54 (m, 2H), 1.50-1.35 (m, 2H), 1.30 (d, J = 6.3 Hz,3H), 0.95 (t, J = 7.2 Hz, 3H).

[0123] Example 2

[0124] Preparation of compound I-02

[0125]

[0126] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of tetrahydrofuran, and cyclobutanol (432 mg, 6 mmol) and sulfuric acid (98%, 196 mg, 1.96 mmol) were added dropwise. The mixture was heated to reflux at 66 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to obtain 471 mg of compound I-02 (yellow-green oil, yield 84.7%). 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (d, J = 15.9 Hz, 1H), 6.77 (s,2H), 6.28 (d, J = 15.9 Hz, 1H), 5.89 (s, 1H), 5.21-5.02 (m, 1H), 3.92 (s,6H), 2.41 (dddt, J = 9.7, 7.9, 7.1, 2.6 Hz, 2H), 2.22-2.05 (m, 2H), 1.84-1.64(m, 2H).

[0127] Example 3

[0128] Preparation of compound I-03

[0129]

[0130] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of tetrahydrofuran, and cyclohexanol (600 mg, 6 mmol) and sulfuric acid (98%, 196 mg, 1.96 mmol) were added dropwise. The mixture was heated to reflux at 66 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting solvent: ethyl acetate: petroleum ether = 2:1 V / V) to obtain 563 mg of compound I-03 (white solid, yield 92.0%). 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (d, J = 15.9 Hz, 1H), 6.77 (s,2H), 6.30 (d, J = 15.8 Hz, 1H), 5.89 (s, 1H), 4.88 (tt, J = 9.0, 4.0 Hz, 1H),3.91 (s, 6H), 1.99-1.75 (m, 4H), 1.7-1.43 (m, 4H), 1.40-1.24 (m, 2H).

[0131] Example 4

[0132] Preparation of compound I-04

[0133]

[0134] In a reaction flask, 4-hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. Thionyl chloride (951 mg, 8 mmol) and 3 drops of DMF were slowly added dropwise to the reaction flask at -15 °C to accelerate the reaction. After the addition was complete, the reaction flask was transferred to room temperature and stirred for 2 hours. The solvent was evaporated by rotary evaporation, and the solution was redissolved in dichloromethane. Phenol (564 mg, 6 mmol) was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. The organic phase was extracted with ethyl acetate and water, and collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation. Normal-phase silica gel column chromatography was performed (eluent: ethyl acetate: petroleum ether = 1:5 V / V) to obtain 522 mg of compound I-04 (white solid, yield 87.0%). 1H NMR (300 MHz, Chloroform-d) δ 7.81 (d, J = 15.8 Hz, 1H), 7.48-7.38 (m, 2H), 7.30-7.24 (m,1H), 7.22-7.17 (m, 2H), 6.86 (s, 2H), 6.52 (d, J = 15.9 Hz, 1H), 5.31 (s,1H), 3.95 (s, 6H).

[0135] Example 5

[0136] Preparation of compound I-05

[0137]

[0138] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of benzyl alcohol, and sulfuric acid (98%, 196 mg, 1.96 mmol) was added dropwise. The mixture was refluxed at 75 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:4 V / V) to obtain 566 mg of compound I-05 (white solid, yield 90.1%). 1 H NMR (300 MHz, Chloroform-d) δ 7.66 (d, J = 15.9 Hz, 1H), 7.49-7.30 (m, 5H), 6.78 (s, 2H), 6.38 (d, J = 15.9 Hz, 1H), 5.91 (s, 1H), 5.26 (s, 2H), 3.91 (s, 6H).

[0139] Example 6

[0140] Preparation of compound I-06

[0141]

[0142] In a reaction flask, 4-hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. At -15 °C, thionyl chloride (951 mg, 8 mmol) and 3 drops of DMF were slowly added dropwise to the reaction flask to catalyze the reaction. After the addition was complete, the mixture was stirred at room temperature for about 2 hours. The reaction solution was evaporated to dryness, dissolved in dichloromethane, and then phenylethanol (293 mg, 2.4 mmol) in dichloromethane was added dropwise. The mixture was stirred at room temperature. After the reaction was completed, normal-phase silica gel column chromatography was performed (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to purify and obtain 425 mg of compound I-06 (white solid, yield 64.8%). 1 H NMR(400 MHz, Chloroform-d) δ 7.61 (d, J = 15.8 Hz, 1H), 7.38-7.24 (m, 5H), 6.78(s, 2H), 6.31 (d, J = 15.9 Hz, 1H), 5.85 (s, 1H), 4.45 (t, J = 7.1 Hz, 2H), 3.93 (s, 6H), 3.04 (t, J = 7.1 Hz, 2H).

[0143] Example 7

[0144] Preparation of compound I-07

[0145]

[0146] In a reaction flask, 4-hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. At -15 °C, thionyl chloride (951 mg, 8 mmol) and 3 drops of DMF were slowly added dropwise to the reaction flask to catalyze the reaction. After the addition was complete, the mixture was stirred at room temperature for about 2 hours. The reaction solution was evaporated to dryness, dissolved in dichloromethane, and then a dichloromethane solution of phenylpropanol (326 mg, 2.4 mmol) was added dropwise. The mixture was stirred at room temperature. After the reaction was completed, normal-phase silica gel column chromatography was performed (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to purify and obtain 442 mg of compound I-07 (white solid, yield 64.6%). 1H NMR(300 MHz, Chloroform-d) δ 7.61 (d, J = 15.9 Hz, 1H), 7.35-7.19 (m, 5H), 6.80(s, 2H), 6.34 (d, J = 15.9 Hz, 1H), 5.89 (s, 1H), 4.25 (t, J = 6.5 Hz, 2H), 3.94 (s, 6H), 2.85-2.70 (m, 2H), 2.15-1.98 (m, 2H).

[0147] Example 8

[0148] Preparation of compound I-08

[0149]

[0150] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of isopropanol, and sulfuric acid (98%, 196 mg, 1.96 mmol) was added dropwise. The mixture was heated to reflux at 83 °C. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:3 V / V) to obtain 523 mg of compound I-08 (white solid, yield 93.4%). 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (d, J = 15.9 Hz, 1H), 6.77 (s, 2H), 6.29 (d, J = 15.9Hz, 1H), 5.90 (s, 1H), 5.13 (m, J = 6.2 Hz, 1H), 3.91 (s, 6H), 1.31 (d, J =6.3 Hz, 6H).

[0151] Example 9

[0152] Preparation of compound I-09

[0153]

[0154] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), HATU (1.14 g, 3 mmol), and DIPEA (387 mg, 3 mmol) were dissolved in 5 mL of anhydrous DMF and stirred in an ice bath for 1.5 h to activate the carboxylic acid. After activation, phenethylamine (290 mg, 2.4 mmol) was added, and the mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to obtain 572 mg of compound I-09 (brown solid, yield 87.5%). 1 H NMR (300MHz, Chloroform-d) δ 7.53 (d, J = 15.5 Hz, 1H), 7.34-7.23 (m, 5H), 6.72 (s,2H), 6.23 (d, J = 15.5 Hz, 1H), 5.83 (t, J = 6.0 Hz, 1H), 3.88 (s, 6H), 3.72-3.63 (m, 2H), 2.90 (t, J = 6.9 Hz, 2H).

[0155] Example 10

[0156] Preparation of compound I-10

[0157]

[0158] In a reaction flask, 4-hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. At -15 °C, thionyl chloride (951 mg, 8 mmol) and 3 drops of DMF were slowly added dropwise to the reaction flask to catalyze the reaction. After the addition was complete, the mixture was stirred at room temperature for about 2 hours. The reaction solution was evaporated to dryness, dissolved in dichloromethane, and a dichloromethane solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (317 mg, 2.4 mmol) was added dropwise. The reaction was stirred at room temperature. After the reaction was completed, normal-phase silica gel column chromatography was performed (eluting agent: ethyl acetate: petroleum ether = 3:1 V / V) to purify and obtain 526 mg of compound I-10 (pale yellow solid, yield 88.3%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.58 (d, J = 15.9 Hz, 1H), 7.04 (s, 2H), 6.55 (d, J = 15.9 Hz, 1H), 4.94 (d, J = 5.2 Hz, 1H), 4.69 (t, J= 5.7 Hz, 1H), 4.20-4.00 (m, 2H), 3.82 (s, J = 4.1 Hz, 6H), 3.72 (d, J = 5.0Hz, 1H), 3.42 (d, J = 5.7 Hz, 2H).

[0159] Example 11

[0160] Preparation of compound I-11

[0161]

[0162] In a reaction flask, 4-hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. At -15 °C, thionyl chloride (951 mg, 8 mmol) and 3 drops of DMF were slowly added dropwise to the reaction flask to catalyze the reaction. After the addition was complete, the mixture was stirred at room temperature for about 2 hours. The reaction solution was evaporated to dryness, dissolved in dichloromethane, and a dichloromethane solution of dimethyl malate (389 mg, 2.4 mmol) was added dropwise. The mixture was stirred at room temperature. After the reaction was completed, normal-phase silica gel column chromatography was performed (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V). The purified product was 611 mg of compound I-11 (colorless oil, yield 83.0%). 1 H NMR(300 MHz, Chloroform-d) δ 7.68 (d, J = 15.9 Hz, 1H), 6.80 (s, 2H), 6.39 (d, J= 15.9 Hz, 1H), 5.83 (s, 1H), 5.65 (dd, J = 6.8, 5.2 Hz, 1H), 3.94 (s, 6H), 3.79 (d, J = 17.3 Hz, 6H), 3.00 (dd, J = 6.0, 2.2 Hz, 2H).

[0163] Example 12

[0164] Preparation of compound I-12

[0165]

[0166] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), HATU (1.14 g, 3 mmol), and DIPEA (387 mg, 3 mmol) were dissolved in 5 mL of anhydrous DMF and stirred in an ice bath for 1.5 h to activate the carboxylic acid. After activation, ammonia (79 mg, 2.4 mmol) was added, and the mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluent: methanol:dichloromethane = 1:30 V / V) to obtain 385 mg of compound I-12 (brownish-yellow solid, yield 86.3%). 1 H NMR (300MHz, Chloroform-d) δ 7.58 (d, J = 15.3 Hz, 1H), 6.76 (s, 2H), 6.71 (s, 1H), 5.91 (s, 1H), 3.92 (s, 6H).

[0167] Example 13

[0168] Preparation of compound I-13

[0169]

[0170] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, and CDI (N,N'-carbonyldiimidazole, 324 mg, 2 mmol), ethylamine hydrochloride (159 mg, 2 mmol), and triethylamine (303 mg, 3 mmol) were added. The mixture was stirred at room temperature for 8 hours, and the reaction was monitored by TLC until it was complete. The solution was evaporated to dryness and purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 3:1 V / V). The purified product was 423 mg of compound I-13 (gray solid, yield 84.3%). 1 H NMR (300 MHz, Methanol-d4) δ 7.44 (d, J = 15.7 Hz, 1H), 6.85 (s, 2H), 6.45 (d, J = 15.7 Hz, 1H), 3.87 (s, 6H), 3.44-3.34 (m, 2H), 1.20 (t, J = 7.3 Hz, 3H).

[0171] Example 14

[0172] Preparation of compound I-14

[0173]

[0174] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), HATU (1.14 g, 3 mmol), and DIPEA (387 mg, 3 mmol) were dissolved in 5 mL of anhydrous DMF and stirred in an ice bath for 1.5 h to activate the carboxylic acid. After activation, propylamine (141 mg, 2.4 mmol) was added, and the mixture was refluxed at 125 °C. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 3:1 V / V) to obtain 452 mg of compound I-14 (brown solid, yield 85.3%). 1 H NMR (300MHz, DMSO-d6) δ 8.79 (s, 1H), 7.97 (t, J = 5.7 Hz, 1H), 7.32 (d, J = 15.6 Hz, 1H), 6.85 (s, 2H), 6.49 (d, J = 15.6 Hz, 1H), 3.79 (s, 6H), 3.12 (q, J = 6.8Hz, 2H), 1.46 (h, J = 7.3 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0175] Example 15

[0176] Preparation of compound I-15

[0177]

[0178] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (1.5 g, 6 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (1.6 g, 12 mmol) and triethylamine (842 mg, 8.32 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was stopped by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1.5:1 V / V). The purified product was 2.15 g of compound I-15 (white solid, yield 93.1%). 1H NMR (300 MHz, Chloroform-d) δ 7.60 (dd, J =15.9, 1.9 Hz, 1H), 6.76 (d, J = 1.7 Hz, 2H), 6.36 (dd, J = 15.8, 1.5 Hz, 1H), 4.30 (qt, J = 8.7, 6.4 Hz, 6H), 3.90 (d, J = 1.7 Hz, 6H), 1.40 (tt, J = 7.1,1.4 Hz, 6H), 1.37-1.32 (m, 3H).

[0179] Example 16

[0180] Preparation of compound I-16

[0181]

[0182] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), HATU (1.14 g, 3 mmol), and DIPEA (387 mg, 3 mmol) were dissolved in 5 mL of anhydrous DMF and stirred in an ice bath for 1.5 h to activate the carboxylic acid. After activation, cyclopropane (136 mg, 2.4 mmol) was added, and the mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluent: methanol:dichloromethane = 1:30 V / V) to obtain 418 mg of compound I-16 (brown solid, yield 79.5%). 1 H NMR (300 MHz, Chloroform-d) δ 7.52 (d, J = 15.6 Hz, 1H), 6.72 (s, 2H), 6.29 (d, J = 15.5Hz, 1H), 6.21-6.08 (m, 1H), 5.88 (s, 1H), 3.87 (s, 6H), 2.86 (tq, J = 7.3,3.7 Hz, 1H), 0.82 (td, J = 7.1, 5.2 Hz, 2H), 0.62-0.54 (m, 2H).

[0183] Example 17

[0184] Preparation of compound I-17

[0185]

[0186] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), HATU (1.14 g, 3 mmol), and DIPEA (387 mg, 3 mmol) were dissolved in 5 mL of anhydrous DMF and stirred in an ice bath for 1.5 h to activate the carboxylic acid. After activation, aniline (223 mg, 2.4 mmol) was added, and the mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by normal-phase silica gel column chromatography (eluting ethyl acetate:petroleum ether = 1:1 V / V) to give 406 mg of compound I-17 (brown solid, yield 91.0%). 1 H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.91 (s, 1H), 7.75-7.66 (m, 2H), 7.52 (d, J = 15.5 Hz, 1H), 7.33 (dd, J = 8.5, 7.3 Hz, 2H), 7.10-7.01 (m, 1H), 6.94 (s, 2H), 6.69 (d, J = 15.6 Hz, 1H), 3.83 (s, 6H).

[0187] Example 18

[0188] Preparation of compound I-18

[0189]

[0190] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg, 2.2 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and then 1,3-propanediol (608 mg, 8 mmol) and DMAP (12 mg, 0.1 mmol) were added. The mixture was heated to reflux at 40 °C. After the reaction was completed by TLC monitoring, the mixture was evaporated to dryness and purified by normal-phase silica gel column chromatography (eluting with ethyl acetate:petroleum ether = 4:1 V / V) to give 425 mg of compound I-18 (pink solid, yield 75.4%). 1H NMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 15.8 Hz,1H), 6.78 (s, 2H), 6.32 (d, J = 15.9 Hz, 1H), 5.96 (s, 1H), 4.39 (t, J = 6.0Hz, 2H), 3.93 (s, 6H), 3.76 (t, J = 5.9 Hz, 2H), 1.97 (q, J = 6.0 Hz, 2H).

[0191] Example 19

[0192] Preparation of compound I-19

[0193]

[0194] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), DMAP (48 mg, 0.4 mmol), and morpholine (209 mg, 2.4 mmol) were dissolved in 3 mL of a mixed solvent of DMF:DCM (v / v) = 1:2. The mixture was stirred at room temperature for 30 minutes. DCC (dicyclohexylcarbodiimide, 495 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for about 12 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 4:1 v / v) to obtain 542 mg of compound I-19 (white solid, yield 92.4%). 1 HNMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 15.3 Hz, 1H), 6.79-6.65 (m, 3H), 5.88 (s, 1H), 3.93 (s, 6H), 3.73 (m, J = 5.5 Hz, 8H).

[0195] Example 20

[0196] Preparation of compound I-20

[0197]

[0198] 4-Hydroxy-3,5-dimethoxycinnamic acid (448 mg, 2 mmol), DMAP (48 mg, 0.4 mmol), and thiomorpholine (247 mg, 2.4 mmol) were dissolved in 3 mL of a mixed solvent of DMF:DCM (v / v) = 1:2. After stirring at room temperature for 30 minutes, DCC (495 mg, 2.4 mmol) was added, and stirring was continued at room temperature for about 12 hours. The reaction was monitored by TLC until it ended. The mixture was extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 4:1 v / v) to obtain 536 mg of compound I-20 (white solid, yield 86.7%). 1 H NMR(300 MHz, Chloroform-d) δ 7.60 (d, J = 15.3 Hz, 1H), 6.76 (s, 2H), 6.69 (d, J= 15.3 Hz, 1H), 5.83 (s, 1H), 3.94 (m, 10H), 2.75-2.64 (m, 4H).

[0199] Example 21

[0200] Preparation of compound I-21

[0201]

[0202] Methyl 3,5-dimethoxy-4-hydroxycinnamate (476 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was stopped by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to give 725 mg of compound I-21 (white solid, yield 96.9%). 1 H NMR (300 MHz, Chloroform-d) δ 7.61 (d, J = 15.9 Hz,1H), 6.76 (s, 2H), 6.41-6.31 (m, 1H), 4.38-4.25 (m, 4H), 3.90 (s, 6H), 3.82(s, 3H), 1.41 (td, J = 7.1, 1.2 Hz, 6H).

[0203] Example 22

[0204] Preparation of compound I-22

[0205]

[0206] 3,5-Dimethoxy-4-hydroxycinnamate propyl ester (532 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to obtain 766 g of compound I-22 (white solid, yield 95.3%). 1 H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J =15.9 Hz, 1H), 6.77 (s, 2H), 6.38 (d, J = 15.9 Hz, 1H), 4.33 (p, J = 7.2 Hz,4H), 4.18 (t, J = 6.7 Hz, 2H), 3.91 (s, 6H), 1.76 (dt, J = 14.2, 7.2 Hz, 2H), 1.41 (td, J = 7.1, 1.2 Hz, 6H), 1.02 (t, J = 7.4 Hz, 3H).

[0207] Example 23

[0208] Preparation of compound I-23

[0209]

[0210] Butyl 3,5-dimethoxy-4-hydroxycinnamate (560 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was stopped by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to give 718 mg of compound I-23 (white solid, yield 86.3%). 1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J = 15.9 Hz,1H), 6.77 (s, 2H), 6.37 (d, J = 15.9 Hz, 1H), 4.32 (p, J = 7.2 Hz, 4H), 4.22(t, J = 6.6 Hz, 2H), 3.90 (s, 6H), 1.71 (dt, J = 14.7, 6.8 Hz, 2H), 1.53-1.44(m, 2H), 1.41 (td, J = 7.1, 1.2 Hz, 6H), 0.98 (t, J = 7.3 Hz, 3H).

[0211] Example 24

[0212] Preparation of compound I-24

[0213]

[0214] Phosphorus oxychloride (1.36 g, 8.88 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (359 mg, 3.55 mmol) was added dropwise. Then, a dichloromethane solution of ethyl 3,5-dimethoxy-4-hydroxycinnamate (448 mg, 1.78 mmol) was slowly added dropwise under ice bath conditions. The mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. Anhydrous sodium sulfate was added, and the solvent was evaporated to dryness to obtain a yellow oil. The oil was dissolved in chloroform and added dropwise to diethyl ether, where a yellow solid slowly precipitated. The mixture was filtered to give 482 mg of compound I-24 (yellow solid, yield 81.7%). 1 H NMR (300 MHz, Chloroform-d) δ 7.56 (dd, J = 16.0, 6.2 Hz, 1H), 6.73 (s, 2H), 6.36 (d, J = 15.9 Hz,1H), 4.28 (q, J = 7.1 Hz, 2H), 3.88 (d, J = 8.1 Hz, 6H), 1.36 (t, J = 7.1 Hz, 3H).

[0215] Example 25

[0216] Preparation of compound I-25

[0217]

[0218] Isopropyl 3,5-dimethoxy-4-hydroxycinnamate (532 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:1.5 V / V) to give 756 mg of compound I-25 (white solid, yield 94.0%). 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (dd, J =15.9, 1.9 Hz, 1H), 6.76 (s, 2H), 6.35 (d, J = 15.9 Hz, 1H), 5.21-5.09 (m,1H), 4.32 (p, J = 7.2 Hz, 4H), 3.90 (d, J = 1.7 Hz, 6H), 1.41 (td, J = 7.1,1.3 Hz, 6H), 1.33 (dd, J = 6.3, 1.6 Hz, 6H).

[0219] Example 26

[0220] Preparation of compound I-26

[0221]

[0222] Phenethyl 3,5-dimethoxy-4-hydroxycinnamate (656 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to give 741 mg of compound I-26 (white solid, yield 79.8%). 1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J = 15.9Hz, 1H), 7.40-7.24 (m, 5H), 6.76 (s, 2H), 6.36 (d, J = 15.9 Hz, 1H), 4.45 (t,J = 7.1 Hz, 2H), 4.41-4.23 (m, 4H), 3.91 (s, 6H), 3.04 (t, J = 7.1 Hz, 2H), 1.42 (td, J = 7.1, 1.2 Hz, 6H).

[0223] Example 27

[0224] Preparation of compound I-27

[0225]

[0226] 684 mg (2 mmol) of phenylpropyl 3,5-dimethoxy-4-hydroxycinnamate was dissolved in 10 mL of carbon tetrachloride. Diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was stopped by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:1.5 V / V) to give 859 mg of compound I-27 (white solid, yield 89.7%). 1 H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J =15.9 Hz, 1H), 7.37-7.20 (m, 5H), 6.78 (s, 2H), 6.38 (d, J = 15.9 Hz, 1H), 4.42-4.20 (m, 6H), 3.92 (s, 6H), 2.77 (dd, J = 8.6, 6.7 Hz, 2H), 2.07 (dq, J= 9.0, 6.7 Hz, 2H), 1.42 (td, J = 7.0, 1.2 Hz, 6H).

[0227] Example 28

[0228] Preparation of compound I-28

[0229]

[0230] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (504 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and dimethyl phosphate (286 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to obtain 651 mg of compound I-28 (white solid, yield 90.4%). 1 H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J = 15.9Hz, 1H), 6.77 (s, 2H), 6.37 (d, J = 15.3 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.95 (d, J = 11.6 Hz, 6H), 3.91 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

[0231] Example 29

[0232] Preparation of compound I-29

[0233]

[0234] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (504 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diisopropyl phosphate (432 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to obtain 726 mg of compound I-29 (white solid, yield 87.2%). 1 H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J = 15.9Hz, 1H), 6.76 (s, 2H), 6.36 (d, J = 15.9 Hz, 1H), 4.87 (dp, J = 7.2, 6.1 Hz,2H), 4.28 (q, J = 7.1 Hz, 2H), 3.89 (s, 6H), 1.40 (t, J = 5.8 Hz, 15H).

[0235] Example 30

[0236] Preparation of compound I-30

[0237]

[0238] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (504 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and di-tert-butyl phosphate (504 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it was complete. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to obtain 855 mg of compound I-30 (white solid, yield 96.2%). 1 H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J = 15.9Hz, 1H), 6.75 (s, 2H), 6.36 (d, J = 15.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.88 (s, 6H), 1.54 (s, 18H), 1.35 (t, J = 7.1 Hz, 3H).

[0239] Example 31

[0240] Preparation of compound I-31

[0241]

[0242] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (504 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and dibenzyl phosphate (681 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour and reacted at room temperature for 16 hours. The reaction was stopped by TLC at this point. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:2 V / V) to obtain 940 mg of compound I-31 (white solid, yield 92.1%). 1H NMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 15.9 Hz, 1H), 7.47-7.31 (m, 10H), 6.77 (s, 2H), 6.39 (d, J = 15.9 Hz, 1H), 5.37-5.24 (m, 4H), 4.29 (q, J = 7.1 Hz, 2H), 3.82 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H).

[0243] Example 32

[0244] Preparation of compound II-01

[0245]

[0246] Ethyl 3,5-dimethoxy-4-hydroxycinnamate (504 mg, 2 mmol) was dissolved in 10 mL of toluene, and 6 mL of diisobutylaluminum hydride was added. The mixture was stirred in an ice bath for about 1 hour. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding 4 mL of anhydrous ethanol. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:1 V / V) to obtain 362 mg of compound II-01 (yellow oil, yield 86.2%). 1 H NMR (300 MHz, Chloroform-d) δ 6.60 (s, 2H), 6.49 (d, J = 15.8 Hz, 1H), 6.22 (dt, J = 15.8, 5.9 Hz, 1H), 4.29 (dd, J = 5.9, 1.4 Hz, 2H), 3.87(s, 6H).

[0247] Example 33

[0248] Preparation of compound II-02

[0249]

[0250] 4-(3-hydroxypropyl-1-enyl)-2,6-dimethoxyphenol (420 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (243 mg, 2.4 mmol), DMAP (2.44 mg, 0.02 mmol), and acetic anhydride (254 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for about 30 minutes, the solvent was evaporated to dryness, and the mixture was extracted with dichloromethane and water. The organic phase was collected, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to normal-phase silica gel column chromatography (eluting solvent: ethyl acetate: petroleum ether = 1:2 V / V). The purified product was 461 mg of compound II-02 (white solid, yield 78.4%). 1 H NMR (400 MHz, Chloroform-d) δ 6.69-6.56 (m, 3H), 6.26 (dt, J = 15.8, 6.5 Hz, 1H), 4.74 (d, J = 6.5 Hz, 2H), 3.85 (s, 6H), 2.36(s, 3H), 2.13 (s, 3H).

[0251] Example 34

[0252] Preparation of compound II-03

[0253]

[0254] 4-(3-hydroxypropyl-1-enyl)-2,6-dimethoxyphenol (504 mg, 2.4 mmol), DMAP (24 mg, 0.2 mmol), and 3,5-di-tert-butyl-4-hydroxybenzoic acid (500 mg, 2 mmol) were dissolved in dichloromethane and stirred at room temperature for 30 minutes. DCC (N,N'-dicyclohexylcarbodiimide, 495 mg, 2.4 mmol) was added, and stirring was continued at room temperature for about 12 hours. The reaction was monitored by TLC until it ended. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:3 V / V) to obtain 585 mg of compound II-03 (white solid, yield 66.1%). 1 H NMR (300 MHz, Chloroform-d) δ 8.10 (s, 2H), 6.70 (s, 2H), 6.61 (d, J = 15.5 Hz, 1H), 6.36 (dt, J = 15.8, 5.6 Hz, 1H), 5.77 (s, 1H), 4.36 (d, J = 4.2 Hz, 2H), 3.84 (s, 6H), 1.51 (s, 18H).

[0255] Example 35

[0256] Preparation of compound II-04

[0257]

[0258] 4-(3-hydroxypropyl-1-enyl)-2,6-dimethoxyphenol (420 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then heated to reflux at 76 °C for 3 days. The reaction was monitored by TLC until it ended. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 2:1 V / V) to obtain 418 mg of compound II-04 (yellow oil, yield 65.7%). 1 H NMR (300 MHz, Chloroform-d) δ 6.64 (s,2H), 6.53 (d, J = 15.8 Hz, 1H), 6.25 (dt, J = 15.8, 5.9 Hz, 1H), 5.63 (s,1H), 4.32 (dd, J = 5.9, 1.4 Hz, 2H), 4.22-4.12 (m, 2H), 3.91 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H).

[0259] Example 36

[0260] Preparation of compound II-05

[0261]

[0262] 4-(3-hydroxypropyl-1-enyl)-2,6-dimethoxyphenol (420 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethyl phosphate (359 mg, 2.6 mmol) and triethylamine (283 mg, 2.8 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then reacted at room temperature for 16 hours. The reaction was monitored by TLC until it ended. The mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was then purified by normal-phase silica gel column chromatography (eluting agent: ethyl acetate: petroleum ether = 4:1 V / V) to obtain 580 mg of compound II-05 (pale yellow solid, yield 83.8%). 1H NMR (400 MHz, Chloroform-d) δ 6.61 (s, 2H), 6.52 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 16.1, 5.6 Hz, 1H), 4.32 (dt, J =13.8, 6.8 Hz, 6H), 3.87 (s, 6H), 2.33 (s, 1H), 1.40 (t, J = 7.1 Hz, 6H).

[0263] Example 37

[0264] prescription:

[0265] Compound I-15: 0.15 g, 0.3 g, or 0.6 g

[0266] 0.9% saline solution as needed

[0267] Add to 100 mL.

[0268] Preparation of I-15 injection: Take 0.15 g, 0.3 g, or 0.6 g of compound I-15, pass it through a 60-mesh sieve, add it to 80 mL of 0.9% physiological saline, shake to dissolve, then add physiological saline to 100 mL, adjust the pH to 5.5-6.5, mix well, add 0.1% activated carbon for adsorption (0.1 g activated carbon per 100 mL of solution), filter through a 0.2 μm microporous membrane, package, and prepare a dosage form of 1 mL or 5 mL with a concentration of 1.5, 3, or 6 mg / mL. Sterilize with flowing steam at 100℃ for 15 minutes.

[0269] Example 38

[0270] A suspension was prepared using sodium carboxymethyl cellulose (CMC-Na) as a suspending agent.

[0271] Prescription (specifications: 1.5, 3, 6 mg / mL):

[0272] Compound I-15: 0.15 g, 0.3 g, or 0.6 g

[0273] Sodium carboxymethyl cellulose 0.5 g

[0274] Add distilled water to a final volume of 100 mL.

[0275] Preparation of I-15 suspension: Take 0.15 g, 0.3 g or 0.6 g of compound I-15 and pass it through a 60-mesh sieve; pass 0.5 g of sodium carboxymethyl cellulose through an 80-mesh sieve. Disperse the sodium carboxymethyl cellulose and dissolve it in 100 mL of distilled water to obtain a 0.5% sodium carboxymethyl cellulose aqueous solution. Before use, disperse and suspend compound I-15 in the 0.5% sodium carboxymethyl cellulose aqueous solution, shake to mix evenly, and prepare a formulation of 1 mL or 5 mL with a concentration of 1.5, 3 or 6 mg / mL.

[0276] Example 39

[0277] prescription:

[0278] Compound I-15: 0.15 g, 0.3 g, or 0.6 g

[0279] Lactose 3.0 g

[0280] 3.0 g corn starch

[0281] 3.5 g of microcrystalline cellulose

[0282] 0.6 mL of 0.5% sodium carboxymethyl cellulose.

[0283] Preparation of I-15 granules: Take 0.15 g, 0.3 g, or 0.6 g of compound I-15 and pass them through a 60-mesh sieve; take 3.0 g of lactose and pass them through an 80-mesh sieve; take 3.0 g of corn starch and 3.5 g of microcrystalline cellulose and pass them through an 80-mesh sieve. Mix I-15 thoroughly with lactose, corn starch, and microcrystalline cellulose, add an appropriate amount of 0.5% sodium carboxymethyl cellulose to form a soft mass, then disperse it into granules using a 20-mesh sieve, and dry it. Each 0.1 g of the preparation contains 1.5, 3, or 6 mg of compound I-15.

[0284] Example 40

[0285] prescription:

[0286] Compound I-15: 0.15 g, 0.3 g, or 0.6 g

[0287] Lactose 3.0 g

[0288] 3.0 g corn starch

[0289] 3.5 g of microcrystalline cellulose

[0290] 0.5% sodium carboxymethyl cellulose 0.6 mL

[0291] Magnesium stearate 0.05g.

[0292] Preparation process of I-15 tablets: Take 0.15 g, 0.3 g, or 0.6 g of compound I-15 and pass them through a 60-mesh sieve; pass 3.0 g of lactose through an 80-mesh sieve; pass 3.0 g of corn starch and 3.5 g of microcrystalline cellulose through an 80-mesh sieve. Thoroughly mix I-15 with lactose, corn starch, and microcrystalline cellulose, add an appropriate amount of 0.5% sodium carboxymethyl cellulose to form a soft mass, then disperse it into granules using a 20-mesh sieve, dry, granulate, add magnesium stearate as a lubricant, and compress into tablets. Each tablet contains 0.1 g of compound I-15, with each tablet containing 1.5, 3, or 6 mg of compound I-15.

[0293] Example 41

[0294] prescription:

[0295] Compound I-15: 0.15 g, 0.3 g, or 0.6 g

[0296] Lactose 3.0 g

[0297] 3.0 g corn starch

[0298] 3.5 g of microcrystalline cellulose

[0299] 0.5% sodium carboxymethyl cellulose 0.6 mL

[0300] Magnesium stearate 0.05g.

[0301] Preparation of I-15 capsules: Take 0.15 g, 0.3 g, or 0.6 g of compound I-15 and pass them through a 60-mesh sieve; take 3.0 g of lactose and pass them through an 80-mesh sieve; take 3.0 g of corn starch and 3.5 g of microcrystalline cellulose and pass them through an 80-mesh sieve. Mix I-15 thoroughly with lactose, corn starch, and microcrystalline cellulose, add an appropriate amount of 0.5% sodium carboxymethyl cellulose to form a soft mass, then disperse it into granules using a 20-mesh sieve, dry it, granulate it, and fill it into size II capsules. Each capsule contains 0.1 g of compound I-15, with each capsule containing 1.5, 3, or 6 mg of compound I-15.

[0302] Example 42

[0303] I-15 (Preparation process:

[0304] prescription:

[0305] Compound I-15 15 g, 30 g or 60 g

[0306] Polyethylene glycol 4000 (PEG4000) 300g

[0307] Sipan 80 4g

[0308] Polyethylene glycol 400 (PEG400) 20g.

[0309] Preparation of I-15 pellets: Compound I-15 is passed through a 60-mesh sieve to obtain fine powder. Excipients PEG4000 and Span 80 are passed through an 80-mesh sieve. PEG4000 is heated to melt (60-70℃), and Span 80 and polyethylene glycol 400 are added. After stirring evenly, the fine powder of compound I-15 is added and stirred for 15 minutes. The mixture is allowed to stand for 0.5-1 hour until the foam dissipates. The mixture is then poured into the storage tank of the pelleting machine (maintained at 70-80℃). The dropping rate is adjusted (50-60 drops / minute), and the pellets are dropped into dimethyl silicone oil at 10-15℃, allowing them to condense into pellets. Surface condensate is absorbed with filter paper, and the pellets are dried and screened for quality (roundness ≥ 0.95, hardness ≥ 20KN). Approximately 5 pellets (0.2g, 0.35g, and 0.5g) contain approximately 15, 30, and 60 mg of I-15, respectively.

[0310] Example 43

[0311] Test Example 1: The conditioned site-preferred efficacy of compounds I-03, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 against methamphetamine.

[0312] The efficacy of methamphetamine in inducing conditioned position preference (CPP) in mice using alternating administration of methamphetamine and saline was evaluated. C57BL / 6J mice (male, 6–8 weeks old, weighing 20±3 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were acclimatized for 7 days under standard feeding conditions (free access to food and water, 12-hour diurnal cycle)

[0313] Animal model establishment: On day 1, all C57 mice were placed sequentially into the CPP chamber and allowed to explore freely for 15 minutes. The time each mouse spent in different chambers on both sides was recorded as baseline data for the pre-test, and the mice were divided into preferred and non-preferred chambers based on the length of their stay. On day 2, C57 mice were injected intraperitoneally with methamphetamine (2 mg / kg, dissolved in saline) and immediately placed in the non-preferred chamber for 30 minutes of training. On day 3, the same volume of saline was injected, and the mice were immediately placed in the preferred chamber for 30 minutes of training. This alternation was repeated four times for a total of eight days of training. On day 9, the same procedure as day 1 was repeated, with mice allowed to explore freely for 15 minutes and the time spent on both sides recorded as post-test data. Finally, the CPP score for each mouse was calculated by subtracting the pre-test time in the non-preferred chamber from the post-test time in the non-preferred chamber. A higher score indicates a higher degree of preference for the induced condition location.

[0314] Conditioned Place Preference (CPP) test: This test evaluated the degree of conditioned place preference induced by methamphetamine in mice. The CPP apparatus consisted of three interconnected chambers (30×15×30 cm / chamber), with black and white striped and gray solid-color visual cue chambers on the sides, and a neutral transition zone (10×15×30 cm) in the middle. Adjustable partitions controlled passage between chambers, and sterile padding was placed on the bottom of each chamber. During the experiment, a constant temperature of 22±1℃, 45% humidity, and <55 dB ambient noise were maintained. After each day's experiment, the chambers were thoroughly cleaned with 75% ethanol to eliminate any residual odor.

[0315] Day 0: Adaptation training. Each mouse freely explores the three chambers of the CPP for 15 minutes to eliminate the stress of the new environment.

[0316] Day 1: Pre-test. Each mouse was placed in a neutral central area and allowed free access to both chambers of the device for 15 minutes. To eliminate the greater influence of strong unconditional preference on the results, mice with a strong unconditional preference for one chamber (i.e., >70% of the time spent in that chamber) and mice with a slight preference for one chamber were excluded from the pre-test. All eligible mice were randomly assigned to groups. In the first conditional position preference screening test, they were divided into a control group, a methamphetamine model group, and groups of compounds I-03, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 (all administered at a dose of 100 mg / kg, prepared by gavage with 0.5% CMC-Na solution). Due to the large number of groups and the large number of animals required for the conditional position preference test, the efficacy was evaluated in two separate tests. The first batch consisted of 7 groups: groups I-03, I-08, I-15, I-17, and I-23, and the model group and control group. Figure 1 The second batch consists of 5 groups: groups I-09, II-02, and I-26, along with the model group and the control group. Figure 2 ).

[0317] On days 2, 4, 6, and 8: The drug intervention group was given the corresponding concentration of the drug by gavage before the methamphetamine injection pairing. The model group and the control group were given 0.5% CMC-Na by gavage as a solvent control before the methamphetamine pairing. 90 min after administration, except for the control group, the mice in the other groups were injected intraperitoneally with 0.2 mg / mL methamphetamine at a volume of 10 mL / kg. They were then placed in the methamphetamine pairing chamber (pre-test non-preference chamber) for 30 min to pair. The control group mice were given the same volume of physiological saline and were also paired in the methamphetamine pairing chamber for 30 min.

[0318] On days 3, 5, 7, and 9: All mice were injected intraperitoneally with saline at a dose of 10 mL / kg and immediately placed in the contralateral saline pairing chamber (pre-test preference chamber) for 30 min for pairing. No drugs were administered before the saline pairing training.

[0319] Day 10: Post-test, each mouse was placed in the central neutral area and allowed free access to the two side chambers of the device for 15 minutes.

[0320] After the test is completed, the CPP score is calculated based on the data exported from the computer behavioral software.

[0321] CPP score = Post-test methamphetamine pairing chamber residence time (s) - Pre-test methamphetamine pairing chamber residence time (s).

[0322] See results Figure 1 , Figure 2 The results showed that, at a dose of 100 mg / kg, the CPP scores of compounds I-08, I-15, and I-26 decreased significantly, approaching the levels of normal mice. This indicates that at this dose, compounds I-08, I-15, and I-26 can significantly alleviate methamphetamine-induced conditional position preference and inhibit its addictive properties. Although compounds I-17 and I-23 showed a decreasing trend, no significant statistical differences were observed.

[0323] Test Example 2: Experiment on the effects of compounds I-03, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 on depressive behavior induced by continuous methamphetamine withdrawal.

[0324] The efficacy of methamphetamine in spontaneous withdrawal models was evaluated in mice after continuous methamphetamine administration. C57BL / 6J mice (male, weighing 20±3 g, 6–8 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were acclimatized for 7 days under standard feeding conditions (free access to food and water, 12-hour diurnal cycle).

[0325] Animal model establishment: C57 mice were intraperitoneally injected once daily with methamphetamine (5 mg / kg, dissolved in physiological saline), while the control group received an equal volume of physiological saline (blank solution) intraperitoneally. After 7 days of continuous administration, administration was stopped, and all mice underwent spontaneous withdrawal in their cages for 14 days. In the screening test for depressive-like behaviors, mice were divided into a control group, a methamphetamine model group, and groups containing compounds I-3, I-08, I-09, II-02, I-15, I-17, I-23, and I-26. Due to the large number of groups and the large number of animals required for the depressive-like behavior test, the efficacy was evaluated in two separate trials. The first batch consisted of 7 groups: I-03, I-08, I-15, I-17, I-23, the model group, and the control group. Figure 3The second batch consists of 5 groups: I-09, II-02, I-26, the model group, and the control group. Figure 4 ).

[0326] Administration method: The treatment groups were administered compounds I-3, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 (100 mg / kg, dispersed in 0.5% CMC-Na solution) by gavage, while the control and model groups were administered an equal volume of 0.5% CMC-Na.

[0327] Forced Swimming Test (FST): The forced swimming test (FST) was used to evaluate desperate behavior in mice. C57 mice were placed in a 5-liter glass beaker (11.8 cm in diameter, 27.5 cm in height) with water level 18-20 cm and water temperature 23-25°C. The mice were visually isolated from each other for 6 minutes. Two single-blind analysts analyzed the time the mice remained still in the water within the first 4 minutes. Activity was defined as swimming and climbing, and stillness was defined as floating or making small paddling motions to keep their heads above water.

[0328] The results showed that the immobility time during swimming was significantly increased in the model group mice. After administration of 100 mg / kg, the immobility time during swimming was significantly decreased in the I-08 and I-15 groups. Figure 3 A) indicates that at this dose, compounds I-08 and I-15 can significantly alleviate depressive-like hopelessness behavior in mice. While the immobility time in other groups showed a decreasing trend ( Figure 3 A, Figure 4 (A), but no significant statistical difference was observed.

[0329] Tail Suspension Test (TST): The TST was used to evaluate desperate behavior in mice. C57 mice were suspended in an open box with a white background, their tails taped shut, with the mice visually isolated from each other for 6 minutes. Two single-blind analysts analyzed the time the mice remained motionless in the air for the first 4 minutes. Activity was defined as large-amplitude swinging and struggling, while stillness was defined as hanging motionless or making small limb movements. Using the same administration method as the forced swimming test, compounds I-3, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 (all at a dose of 100 mg / kg) were screened for their effects on tail suspension and struggling behavior. The results were recorded to observe the therapeutic effects.

[0330] The results showed that the tail immobility time in the model group mice was significantly increased. After administration of 100 mg / kg, the tail immobility time in groups I-08, I-15, and I-23 was significantly decreased. Figure 3B) indicates that at this dose, compounds I-08, I-15, and I-23 can significantly alleviate depressive-like hopelessness behavior in mice. While the tail immobility time in other groups showed a decreasing trend ( Figure 3 , Figure 4 However, no significant statistical differences were observed.

[0331] Conclusion: A comprehensive analysis of depressive / anxiety-like behaviors revealed that compounds I-3, I-08, I-09, II-02, I-15, I-17, I-23, and I-26 had a regulatory effect on methamphetamine-induced conditioned position preference (CPP), tail suspension time (TST), and swimming time (FST). Compounds I-08 and I-15 significantly improved methamphetamine-induced conditioned position preference and depressive and anxiety-like behaviors in spontaneous withdrawal mice after addiction. This demonstrates their effectiveness in alleviating methamphetamine-induced addiction, depression, and anxiety-like behaviors.

[0332] Test Example 3: Experiment on the effects of derivatives I-08, II-02, I-15, and I-26 on anxiety-like behaviors induced by continuous methamphetamine withdrawal.

[0333] The efficacy of methamphetamine in spontaneous withdrawal mice after continuous administration was evaluated. C57BL / 6J mice (male, 6–8 weeks old, weighing 20±3 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were acclimatized for 7 days under standard feeding conditions (free access to food and water, 12-hour diurnal cycle).

[0334] Animal model establishment: C57 mice were administered methamphetamine (dissolved in physiological saline) once daily via intraperitoneal injection at a dose of 5 mg / kg, while the control group received an equal volume of physiological saline. After 7 days of continuous administration, administration was discontinued, and all mice underwent spontaneous withdrawal in their cages for 14 days. A screening experiment was first conducted, dividing the mice into a control group, a methamphetamine model group, and groups I-08, II-02, I-15, and I-26 (all administered at a dose of 100 mg / kg). After 7 days of continuous administration, behavioral experiments were performed, and the results were recorded to observe the therapeutic effect.

[0335] Administration method: The treatment groups were administered compounds I-08, II-02, I-15, and I-26 (100 mg / kg, dispersed in 0.5% CMC-Na solution) by gavage, while the control and model groups were administered an equal volume of 0.5% CMC-Na.

[0336] Elevated Cross Maze Test (EPM): The EPM test was used to assess anxiety-like behavior in mice. The experimental setup consisted of two opposing open arms and two opposing closed arms (arms approximately 30 cm long and 5 cm wide), with the overall height of the setup approximately 50 cm. Mice were acclimatized to a behavioral laboratory environment for at least 30 minutes before the experiment. During the test, a single mouse was gently placed in the central intersection area of ​​the maze, with its head facing one of the open arms, and allowed to explore freely for 6 minutes. The mouse's behavior was recorded using a video tracking system, and analysis software recorded the number of times the mouse entered the open and closed arms in the last 4 minutes, as well as the time spent in each arm. A decrease in the time spent in the open arms and the number of entries was generally considered to reflect enhanced anxiety-like behavior, while activity in the closed arms reflected approach-avoidance behavior. After the experiment, the maze setup was cleaned with 75% ethanol to avoid residual odor interfering with subsequent experiments.

[0337] The results showed that the open-arm residence time of mice in the model group was significantly reduced. After administration of 100 mg / kg, mice in group I-15 showed significant changes, while mice in groups I-08, I-09, and II-02 showed an increasing trend in open-arm residence time after administration (…). Figure 5 (A), but no significant statistical difference was observed.

[0338] Open Field Test (OFT): The open field test (OFT) was used to assess the spontaneous activity and anxiety-like behaviors of mice. The experimental setup was an open square open field box (approximately 60 cm × 60 cm × 50 cm), with the bottom divided into a central area and a peripheral area. Mice were transferred to a behavioral laboratory for at least 30 minutes to acclimatize before the experiment. During the test, a single mouse was gently placed in the central area of ​​the open field device and allowed to explore freely for 5 minutes. The mouse's movement was recorded using a video tracking system. Behavioral analysis software recorded the time the mouse spent in the central area, the number of times it entered the central area, and the total distance traveled. Reduced activity time in the central area was generally considered to be associated with enhanced anxiety-like behaviors. After each mouse was tested, the open field device was thoroughly cleaned with 75% ethanol to eliminate odor interference.

[0339] The results showed that the central dwell time in the model group mice was significantly decreased. A significant change was observed in mice in group I-15 after administration of 100 mg / kg, while the central dwell time in groups I-08, II-02, and I-26 showed an increasing trend after administration (…). Figure 5 (B), but no significant statistical difference was observed.

[0340] Conclusion: Oral administration of compound I-15 significantly improved anxiety-like behavior.

[0341] Test Example 4: Effects of oral and injectable administration of compounds I-15 and I-08 on methamphetamine-induced conditioned position preference.

[0342] Test Example 1 revealed that compounds I-08 and I-15 significantly improved addiction and post-withdrawal depression / anxiety-like behaviors in model mice. Furthermore, I-15 exhibited good water solubility (approximately 0.35 g / 100 mL saturated solubility in water at 25°C; compound I-08 showed poor water solubility, approximately 0.01 g / 100 mL saturated solubility), making it highly suitable for injection formulation. Preliminary studies also showed good efficacy even with significantly reduced injection dosages. Therefore, compound I-15 was selected for further investigation of its efficacy at different dosages and formulations.

[0343] The methamphetamine-induced conditional position preference (CPP) test was conducted using the same method as in Test Example 1. The six groups were: control group, methamphetamine model group, low-dose I-15 (60 mg / kg), high-dose gavage administration group (120 mg / kg), I-15 injection (iv, 20 mg / kg), and the parent compound 4-hydroxy-3,5-dimethoxycinnamic acid (LA) gavage administration group (50 mg / kg, calculated in equimolar ratio with I-15).

[0344] On days 2, 4, 6, and 8, the four drug intervention groups were given the corresponding dose of the drug by gavage before methamphetamine injection for pairing. The model group and the control group were given 0.5% CMC-Na by gavage as a solvent control before methamphetamine pairing. 90 min after administration, except for the control group, the other five groups of mice were injected intraperitoneally with 0.2 mg / mL methamphetamine at a volume of 10 mL / kg, and then placed in the methamphetamine pairing chamber (pre-test non-preference chamber) for pairing for 30 min. The control group was given the same volume of physiological saline and also paired in the methamphetamine pairing chamber for 30 min.

[0345] On days 3, 5, 7, and 9: All mice were injected intraperitoneally with saline at a dose of 10 mL / kg and immediately placed in the contralateral saline pairing chamber (pre-test preference chamber) for 30 min for pairing. No drugs were administered before the saline pairing training.

[0346] The test will be conducted on the 10th day, and the CPP score will be calculated.

[0347] The results showed that both oral administration of 120 mg / kg and injection of 20 mg / kg to mice in group I-15 significantly reduced the CPP score in the model group mice. Figure 6While I-15 administered via gavage at a lower dose, or the parent drug LA administered via gavage at 50 mg / kg, showed some improvement, statistical analysis revealed no significant difference. This demonstrates that injection administration can significantly reduce the dosage, achieving the same effect as gavage administration at higher doses.

[0348] Conclusion: Compound I-15 significantly improves the positional preference under high-dose gavage or reduced-dose injection conditions; furthermore, when the injection dose is significantly lower than the gavage dose, it can achieve similar or even stronger efficacy than high-dose gavage administration, demonstrating that injection administration has a more significant advantage.

[0349] Test Example 5: Treatment Experiment of Depression and Anxiety-like Behavioral Depression Induced by Methamphetamine Withdrawal After Continuous Administration of Compounds I-15 and I-08 via Gavage and Injection

[0350] The efficacy of antidepressants was evaluated in mice using the same method as in a spontaneous withdrawal model mouse model following continuous methamphetamine administration. Seven groups were established: a blank control group, a methamphetamine model group, a low-dose I-15 (60 mg / kg) and a high-dose I-15 gavage group (120 mg / kg), an I-15 injection group (iv, 20 mg / kg), a parent compound (4-hydroxy-3,5-dimethoxycinnamic acid, LA) gavage group (50 mg / kg, calculated as an equimolar ratio with compound I-15), and a positive control group (fluoxetine, FLX) injection group (iv, 20 mg / kg). I-15 and LA were dispersed in 0.5% CMC-Na solution and administered by gavage at the prescribed doses. The control and model groups were administered an equal volume of 0.5% CMC-Na by gavage. I-15 and fluoxetine were dissolved in physiological saline and injected separately. Behavioral experiments were conducted 7 days after administration, and the effects were observed and recorded.

[0351] The forced swimming test (FST) was performed using the same method as in Test Example 1 above. Results showed that the immobility time in the model group mice was significantly increased compared to the control group, while both injection of I-15 and high-dose gavage of I-15 significantly reduced the immobility time. Figure 7 A), similar to the effects of fluoxetine injection, I-15 injection and high-dose gavage can alleviate hopeless depression / anxiety-like behaviors.

[0352] The tail suspension test (TST) was performed using the same method as in Test Example 1 above. Results showed that the tail suspension immobility time in the model group mice was significantly increased compared to the control group. Except for LA, all other groups showed a reduction in tail suspension immobility time, with I-15 injection showing the best effect. Figure 7 B).

[0353] The open field test (OFT) was performed using the same method as in Test Case 1, evaluating the anxiety level of mice after 7 consecutive days of drug administration. Results showed that the time spent in the central region by the model group mice was significantly reduced compared to the control group, while the time spent in the central region by the high-dose I-15 gavage administration group, the I-15 injection group, and the positive control injection group (FLX) was significantly increased. Figure 8 A), sinapic acid (LA), and low-dose intragastric administration of I-15 were slightly less effective. Meanwhile, the total movement distance of mice in each group after administration was not significantly different from that in the model group. Figure 8 B) indicates that none of the compounds affected the mice's own motor ability.

[0354] The elevated cruciate maze test (EPM) was performed using the same method as in Test Case 1, evaluating the anxiety level of mice after 7 consecutive days of drug administration. Results showed that the model group mice had a significantly shorter time spent in the open arm position compared to the control group. The model mice in the high-dose I-15 gavage group, the low-dose I-15 injection group, and the positive control injection group (FLX) all had significantly longer time spent in the central region. Figure 8 C), sinapic acid (LA), and low-dose I-15 showed slightly weaker effects. Meanwhile, the total movement distance of mice in each group after administration was not significantly different from that in the model group. Figure 8 (D) indicates that none of the drugs affected the mice's own motor ability.

[0355] Conclusion: Compound I-15 significantly improved the effects of high-dose gavage or reduced-dose injection on methamphetamine addiction and spontaneous withdrawal-induced depression and anxiety-like behaviors in mice. Furthermore, the injection dose was significantly lower than the gavage dose, achieving similar or even stronger efficacy than the high-dose gavage administration, demonstrating the more significant advantages of injection administration.

Claims

1. Styrene compounds or their stereoisomers, deuterated derivatives, and pharmaceutically acceptable salts with structures as shown in Formula III: ； in, R 1 R 2 R 3 Each group is independently selected from hydrogen, hydroxyl, alkoxy, or phosphate ester groups; L is selected from carbonyl or methylene; X is selected from O; R 4 Selected from hydrogen, C1 to C 10 Straight-chain or branched alkyl groups, C3-C 10 Cycloalkyl, aromatic alkyl, hydroxyalkyl, or carbonylalkyl; But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, ;R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

2. The styrene compound or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts according to claim 1, characterized in that: R 1 Selected from C1 to C4 alkoxy groups; R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from C1-C4 alkyl, benzyl, R 6 Selected from hydrogen, C1-C4 alkyl, and benzyl; R 3 Selected from C1 to C4 alkoxy groups; L is selected from carbonyl or methylene; X is selected from O; R 4 Selected from hydrogen, C1-C6 straight-chain or branched alkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C6-C 10 Arylalkyl; But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, ;R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

3. The styrene compound or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts according to claim 2, characterized in that: R 1 Selected from methoxy groups; R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from C1-C4 alkyl, benzyl, R 6 Selected from hydrogen, C1-C4 alkyl, and benzyl; R 3 Selected from methoxy groups; L is selected from carbonyl or methylene; X is selected from O; R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, 3-hydroxypropyl, phenethyl, phenylpropyl, 3,5-di-tert-butyl-4-hydroxybenzoyl; But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, phenethyl, phenylpropyl; R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen; Preferred, R 1 Selected from methoxy groups; R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, R 6 Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, and benzyl; R 3 Selected from methoxy groups; L is selected from carbonyl group; X is selected from O; R 4 Selected from methyl, ethyl, n-propyl, isopropyl, cyclobutyl, 3-hydroxypropyl, phenethyl, and phenylpropyl; R 1 Selected from methoxy groups; R 2 Selected from hydroxyl, dihydroxyphosphoryloxy, formula The dialkoxyphosphoryloxy group shown; R 5 Selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, R 6 Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, and benzyl; R 3 Selected from methoxy groups; L is selected from methylene; X is selected from O; R 4 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclobutyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, acetyl, 3,5-di-tert-butyl-4-hydroxybenzoyl, dimethyl malate, morpholinyl, thiomorpholinyl, 3,5-di-tert-butyl-4-hydroxybenzoyl; But excluding: R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from methyl, ethyl, n-propyl, isopropyl; R 1 Selected from methoxy, R 2 Selected from hydroxyl, R 3 Selected from methoxy, L selected from methylene, X selected from O, R 4 Selected from hydrogen.

4. Styrene compounds or their stereoisomers with the structures shown below, and pharmaceutically acceptable salts: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 5. Styrene compounds or their stereoisomers with the structures shown below, and pharmaceutically acceptable salts thereof: 。 6. A method for preparing the styrene phosphate compound according to claim 1, characterized in that: include: When L is selected from carbonyl, R 2 Selected from hydroxyl, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows: ； Among them, R 4 As described in claim 1; Including: 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIa; When L is selected from carbonyl, R 2 Selected from formula The dialkoxyphosphoryloxy group shown, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows: ； Among them, R 2 R 4 R 5 R 6 As described in claim 1; include: Step (1), 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIa; Step (2): Using carbon tetrachloride as the reaction solvent, in the presence of triethylamine, a styrene compound with the structure shown in formula IIIa reacts with... The dialkyl phosphite shown undergoes a phosphorylation reaction to generate a styrene-like compound with the structure shown in Formula IIIb. When L is selected from carbonyl, R 2 Selected from dihydroxyphosphoryloxy, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows: ； Among them, R 4 As described in claim 1; include: Step (1), 4-hydroxy-3,5-dimethoxycinnamic acid and R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIa; Step (2): Using dichloromethane as the reaction solvent, in the presence of triethylamine, a styrene compound with the structure shown in Formula IIIa reacts with phosphorus oxychloride to generate a styrene compound with the structure shown in Formula IIIc. When L is selected from methylene, R 2 Selected from formula The dialkoxyphosphoryloxy group shown, R 1 R 3 Each is independently selected from methoxy groups, and X is selected from O and R. 4 When hydrogen is selected, the synthetic route is as follows: ； Among them, R 5 R 6 As mentioned above; include: Step (1), Reduction reaction: Using diisobutylaluminum hydride as a reducing agent and toluene as a reaction solvent, ethyl 3,5-dimethoxy-4-hydroxycinnamate undergoes a reduction reaction to generate compound 5; Step (2), Phosphorylation reaction: Using carbon tetrachloride as the reaction solvent, in the presence of triethylamine, compound 5 reacts with... The dialkyl phosphite shown undergoes a phosphorylation reaction to generate a styrene-like compound with the structure shown in Formula IIId; When L is selected from methylene, R 2 Selected from hydrogen, R 1 R 3 When the components are independently selected from methoxy groups and X is selected from O, the synthetic route is as follows: ； R 4 As mentioned above; include: Step (1), Reduction reaction: Using diisobutylaluminum hydride as a reducing agent and toluene as a reaction solvent, ethyl 3,5-dimethoxy-4-hydroxycinnamate (compound 4) undergoes a reduction reaction to generate compound 5; Step (2), esterification reaction: using dichloromethane as the reaction solvent and DMAP as the catalyst, in the presence of DCC, compound 5 reacts with R 4 OH undergoes esterification to produce styrene compounds with structures as shown in formula IIIe.

7. The use of the styrene compounds or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts according to any one of claims 1-5 in the preparation of medicaments for the prevention and / or treatment of methamphetamine addiction and for the relief of depression and anxiety-like behaviors following methamphetamine withdrawal.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition is formulated as a pharmaceutically acceptable preparation using styrene compounds or their stereoisomers, deuterated compounds, or pharmaceutically acceptable salts as the main active ingredients, along with pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, characterized in that: The preparations are tablets, capsules, granules, solutions, suspensions, or injections.

10. The use of styrene compounds or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts with the structure shown in Formula III in the preparation of drugs for the prevention and / or treatment of methamphetamine addiction and for the relief of depression and anxiety-like behaviors following methamphetamine withdrawal; ； in, R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L selected from carbonyl, X selected from O, R 4 Selected from isopropyl, sec-pentyl, cyclohexyl, phenyl, benzyl, phenethyl, phenylpropyl, 1,2-propanediol, and dimethyl malate; R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L from carbonyl, X from NH, R 4 The derivative is selected from hydrogen, ethyl, n-propyl, cyclopropyl, phenyl, phenethyl, or X is selected from N, and X is related to R. 4 Cyclic formation to form morpholino or thiomorpholino; R 1 Selected from methoxy, R 2 Selected from hydrogen, R 3 Selected from methoxy, L from methylene, X from carbonyl, R 4 Selected from hydrogen; R 1 Selected from methoxy, R 2 Selected from acetoxy, R 3 Selected from methoxy, L from methylene, X from carbonyl, R 4 Selected from acetyl groups.

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